Loss of TRAF2 Impairs Alloreactive CD4+ T Cells and Maintains Tregs to Favour Islet Allograft Survival Without Exogenous Immunosuppression.

Abstract

The signaling molecule, TNF-receptor associated factor 2 (TRAF2) integrates multiple TNF-family signaling pathways critical for T cell activation suggesting TRAF2 may be a potential target for promoting allograft survival.Here, the role of TRAF2 in T cell responses towards allografts is examined using T cell specific TRAF2-deficient mice (TRAF2TKO). TRAF2TKO mice permanently accepted the majority of full MHC-mismatched islet allografts and display delayed rejection of vascular heterotopic heart and skin allografts without exogenous immunosuppression. Further, TRAF2TKO failed to proliferate in an in vitro MLR - thus TRAF2 deficiency impairs the alloimmune response. Loss of TRAF2 resulted in diminished CD4+ T cell activation as shown by reduced proliferation and decreased expression of activation markers CD44 and CD25 and effector molecules granzyme B and IFN-gamma in response to alloantigen. Further, under Th1 polarizing conditions, TRAF2TKO CD4+ T cells showed abnormal expression of the Th2 cytokine IL-13. Furthermore, TRAF2TKO CD4+ T cells more readily converted to a Treg phenotype in the presence of TGF-beta; and in vivo TRAF2TKO mice harbored increased Tregs. TRAF2 deficiency delayed activation of TNF-induced JNK and NF-kB in T cells. Therefore TRAF2 coordinates extracellular signals from TNF-family ligands to maintain T cell lineage selection and effector function.